Racial disparities in breast cancer clearly exist between European American (EA) and African American (AA) women, but the underlying mechanisms are unknown. The proposed study is designed to investigate whether high prevalence of functional human endogenous retrovirus (HERV) in women of African descent contributes to disparities in age at onset and aggressiveness of breast cancer between AA and EA women. HERV sequences are the remnants of ancient germ line infections by retrovirus in the human genome. Although the majority of HERVs are disabled due to mutation, some of HERVs are still transcriptionally active and have the potential to interfere with host function and cause disease such as cancer. Among them, HERV-K113 and - K115 are of particular interest in relation to breast cancer, because: (1) both show remarkable intact structure of provirus and retain the ability to encode functional retrovirus protein; (2) both display high genetic homology to mouse mammary tumor virus (MMTV), a retrovirus capable of causing mammary tumors in mice; (3) both are insertional polymorphic, showing a clear racial disparity in their prevalence between African and European populations. During breast tumorigenesis, HERVs can be activated to express oncogenic or immunosuppressive proteins, which in turn contribute to tumorigenesis. Expression of HERVs in breast cancer cells appears to be substantially enhanced by treatment with estrogens and other steroids. Considering the significant differences in hormonal and reproductive factors between AA and EA women, it is possible that many known hormone-related exposures that are risk factors for breast cancer (such as age at first full-term pregnancy, parity, early menarche, and late menopause), may interact with HERVs to contribute to breast cancer. Our hypothesis is that the prevalence of HERV-K113 and -K115 insertional polymorphism differs between AA and EA women, and that this differential distribution is associated with breast cancer risk, as well as disparities in breast cancer characteristics. The proposed study will access distribution of insertional polymorphisms of HERV-K113 and -K115 among AA and EA women, to examine their association with breast cancer risk (Aim1) and early-onset and aggressive characteristics (Aim2) in EA and AA women in consideration of interactions with hormone-related factors (Aim3). The study will be nested in the ongoing multi-center case-control study of breast cancer in AA and EA women, and a total of 1600 AA women and 1600 EA women will be included. This is the first large-scale epidemiologic study to investigate the role of HERV in human cancer. We are also the first ones to investigate the association between insertional polymorphism of HERVs and breast cancer in the context of racial disparity. The findings will provide valuable information for understanding the preponderance of early onset, aggressive breast cancer among AA women, and help target high risk populations and lead to potential intervention strategies for those most at risk.